JP2017522359A - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- JP2017522359A JP2017522359A JP2017505530A JP2017505530A JP2017522359A JP 2017522359 A JP2017522359 A JP 2017522359A JP 2017505530 A JP2017505530 A JP 2017505530A JP 2017505530 A JP2017505530 A JP 2017505530A JP 2017522359 A JP2017522359 A JP 2017522359A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- group
- halo
- optionally substituted
- aryl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 120
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 203
- 125000003118 aryl group Chemical group 0.000 claims abstract description 50
- 125000005843 halogen group Chemical group 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 31
- 150000002148 esters Chemical class 0.000 claims abstract description 23
- 239000012453 solvate Substances 0.000 claims abstract description 23
- 229940002612 prodrug Drugs 0.000 claims abstract description 20
- 239000000651 prodrug Substances 0.000 claims abstract description 20
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 17
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims abstract description 13
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 13
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 11
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 8
- 125000004429 atom Chemical group 0.000 claims abstract description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
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- 238000011282 treatment Methods 0.000 claims description 35
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Description
哺乳類細胞は、リン脂質を構造特異的な方法で加水分解して、無数の生成物を生じる、多数のホスホリパーゼを含む。その生成物の多くは、生物学的活性を有する可能性がある。これらの酵素を特定するのに、非常に興味が持たれていた。というのも、これらの、炎症の脂質メディエータの生成の役割のためである。20年前の最初の研究では、哺乳類細胞は、アラキドン酸に特異的な心臓収縮性(cystolic)カルシウム依存性ホスホリパーゼA2(cPLA2)を含むことを示し、大量の証拠により、エイコサノイドの生産のため、アラキドン酸を放出するのを仲介する重要な酵素としてのcPLA2の一番の役割が実証された。
本発明者らは、特定の2−オキソチアゾールが、理想的なcPLA2阻害剤であり、慢性炎症性疾患の治療への新規な治療的ルートを提供することを、驚いたことに見出した。
R7は、R6について定義したとおりであり;または
R6およびR7は、これらと結合した原子と一緒になって、4つまでのR8基で任意に置換された、6員の芳香族もしくは非芳香族、飽和もしくは不飽和、炭素環式もしくはヘテロ原子含有(例えば、O、NまたはS含有)環を形成してもよく;
各R8は、R6について定義したとおりであるか、またはオキソであり;
R10は、C1-6アルキルであり;
Arは、C6-14アリール基であり、前記アリール基は、1以上のR9基で任意に置換されてもよく(好ましくはOに対してメタ位またはパラ位に);
各R9は、ハロ(halo)、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、1以上のハロで任意に置換されたフェニル、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3、好ましくは1であり;
各pは、0〜3である。
R7は、R6について定義したとおりであり;または
R6およびR7は、これらと結合した原子と一緒になって、4つまでのR8基で任意に置換された、6員の芳香族もしくは非芳香族、飽和もしくは不飽和、炭素環式もしくはヘテロ原子含有(例えば、O、NまたはS含有)環を形成してもよく;
各R8は、R6について定義したとおりであるか、またはオキソであり;
R11は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、ここで前記アリール基は、1以上のR9基で置換され(好ましくはOに対してメタ位またはパラ位に);
各R9は、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3、好ましくは1であり;
各pは、0〜3である。
R7は、R6について定義したとおりであり;または
R6およびR7は、これらと結合した原子と一緒になって、4つまでのR8基で任意に置換された、6員の芳香族もしくは芳香族、飽和もしくは不飽和、炭素環式もしくはヘテロ原子含有(例えば、O、NまたはS含有)環を形成してもよく;
各R8は、R6について定義したとおりであるか、またはオキソであり;
R10は、C1-6アルキルであり;
Arは、C6-14アリール基であり、ここで前記アリール基は、1以上のR9基で任意に置換されてもよく(好ましくはOに対してメタ位またはパラ位に);
各R9は、ハロ、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、SC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3、好ましくは1であり;
各pは、0〜3である。
R7は、R6について定義したとおりであり;または
R6およびR7は、これらと結合した原子と一緒になって、4つまでのR8基で任意に置換された、6員の芳香族もしくは非芳香族、飽和もしくは不飽和、炭素環式もしくはヘテロ原子含有(例えば、O、NまたはS含有)環を形成してもよく;
各R8は、R6について定義したとおりであるか、またはオキソであり;
R11は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、ここで前記アリール基は、1以上のR9基で置換され(好ましくはOに対してメタ位またはパラ位に);
各R9は、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、OAr2、O(CH2)qAr2、SC1-10アルキル、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3、好ましくは1であり;
各pは、0〜3である。
R12は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、ここで前記アリール基は、1以上のR9基で任意に置換されてもよく(好ましくはOに対してメタ位またはパラ位に);
各R9は、ハロ、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3であり;
点線は、任意の二重結合である。
R7は、HまたはC1-6アルキルであり;
R11は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、ここで、前記アリール基は、1以上のR9基で任意に置換されてもよく(好ましくは、V1に対してメタまたはパラ位に);
Arは、C6-14アリール基であり、ここで、前記アリール基は、1以上のR9基で任意に置換されてもよく(好ましくはOに対してメタ位またはパラ位に);
各R9は、ハロ、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3である。
本明細書において、特に明記しない限り、用語「アルキル」は、 直鎖および分岐鎖の両方のアルキル基を含み、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、i−ブチル、s−ブチル、t−ブチル、n−ペンチル、i−ペンチル、t−ペンチル、neo−ペンチル、n−ヘキシルまたはi−ヘキシル、t−ヘキシルであってもよい。いずれのアルキルであっても、直鎖が好ましい。
本発明は、慢性炎症性疾患および過剰増殖性疾患の治療において有用性を有する、一連の関連化合物に関する。
最初の実施形態において、本発明は、前記に定義した、式(I)または(I’)
R1およびR3は、それぞれ独立して、H、ハロ(たとえば、フルオロまたはクロロ)、C6-10アリール、C7-12アリールアルキル、C2-12アルケニル;OC1-10アルキル、C1-10−O−C1-10アルキル、OC1-10−O−C1-10アルキル、OC2-10アルケニルまたはC1-10アルキル基から選択される。R1およびR3は、また、SC1-10アルキルであってもよい。
R3は、H、ハロまたはOC1-6アルキルであるのが好ましい。アルキル基は、直鎖状であるのが好ましい。
第2の実施形態において、目的の化合物は、前記において定義した式(II)または(II’)のもの、またはその塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグである。
R9は、−OC1-10アルキル−O−C10アルキル、−OAr2、−O(CH2)qAr2、SAr2またはS(CH2)qAr2(またはR9はまた、SC1-10アルキルであってもよい)であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1から3であり、好ましくは1であり;
各pは、0から3である。アルキル基は、直鎖状が好ましい。
式(IIa)および(IIb)化合物またはその塩を含む。
また、好ましくは、
興味ある、さらなる化合物は、ここに定義するように、式(III)のもの、またはその塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグである。
化合物(III’)において、R1およびR3の一つが、最も好ましくはR1が、C4-10アルキル基、特にC6-8アルキル基(例えばC8アルキル基)、またはC6-10アリール基または−C1-10アルキル−O−C1-10アルキルであるのが好ましい。R1およびR3は、異なるのが好ましい。アルキル基は、直鎖状であるのが好ましい。
さらに好ましい実施形態において、本発明は、ここに定義した式(IV)の化合物またはその塩に関する。
化合物(IV’)において、R1およびR3の一つ、もっとも好ましくはR1が、C4-10アルキル基、特にC6-8アルキル基(例えばC8アルキル基)またはC6-10アリール基であるのが好ましい。R1およびR3は、異なるのが好ましい。
本発明の化合物の製造には、文献公知の反応を典型的に含む。たとえば、請求した化合物の多くの前駆体である2−オキソチアゾールの生成は、塩基存在下におけるチアゾールとアルデヒドXCOHの反応、次いで、ヒドロキシルをケトンへ酸化することにより達成できる。前記X基は、所望の側鎖基またはその前駆体を形成するために選択することが明白である。
本発明の化合物は、慢性炎症性疾患、特にホスホリパーゼ阻害と関連するものの、予防または治療において用いることができる。
別の観点において、本発明は、細胞の成長を予防または阻害することが望ましい(または利益になるかもしれない)場合である疾患または臨床的状況の管理、治療または予防において使用するための本発明の化合物を提供する。例には、腫瘍、癌、新生物組織、ならびに他の前がん状態(premaligant)および非腫瘍性(noneoplastic)過剰増殖性疾患を含み、これらのすべては共に、過剰増殖性疾患または過形成性疾患として、ここでは、言及される。
過剰増殖性疾患における症状を治療する、防止する、または軽減するための本発明の方法において用いるための適切な化合物は、1以上の本発明の化合物により接触された場合に、細胞増殖において変化が検出されることを意図する、異なる方法論の1または組み合わせにより、選択することができる。そのような評価の非制限的例は、以下に示す。
Patel MI, Singh J, Niknami M, Kurek C, Yao M, Lu S, Maclean F, King NJ, Gelb MH, Scott KF, Russell PJ, Boulas J, Dong Q.
別のアプローチにおいて、cPLA2−アルファの発現は、逆転写−PCR、ウエスタンブロット法、および免疫細胞化学により、前立腺癌細胞において決定することができる。成長阻害、アポトーシス、およびcPLA2−アルファ活性は、cPLA2−アルファ低分子干渉RNAまたは阻害剤(Wyeth−1)で阻害した後に、決定することができる。細胞質PLA2−アルファ阻害剤または賦形剤は、前立腺癌マウス異種移植モデルへ投与することもできる。最終的に、リン酸化されたcPLA2−アルファの発現は、ヒトの正常なアンドロゲン感受性の、およびアンドロゲン非感受性の前立腺癌試料において、免疫組織化学により決定することができる。
それらの意図する用途に関わらず、本発明の化合物は、医薬的に許容される組成物に製剤化されるのが好ましい。本発明の組成物に関連して使用される用語「医薬的に許容される」は、生理学的に耐えられ、哺乳類(例えば、ヒト)に投与した際に有害な反応を典型的には生じない、そのような組成物の分子実体および他の成分を指す。ここで用いるように、好ましくは、用語「医薬的に許容される」は、連邦政府もしくは州政府の規制機関により承認されるか、または、米国薬局方または他の一般的に認識された哺乳類における使用のための薬局方、より特定にはヒトにおける薬局方において挙げられることを意味する。
(i)哺乳類において疾患の進行の臨床的症状の発現を防止するか、または遅延させること;
(ii)疾患を阻害すること、すなわち、疾患またはその再発または臨床的または亜臨床的なその症状の少なくとも1つの進行を、停止すること、または遅延させること、または
(iii)疾患の臨床的または亜臨床的な症状の1またはそれ以上を軽減するか、または弱めること。
化合物は、動物対象、特に哺乳類、より詳細には、ヒトまたは疾患のためのモデルとして機能する動物(例えば、マウス、サル等)に対して、用いることができる。
「有効量」は、状態、障害または疾患を処置するために、動物に投与する際、そのような治療を引き起こすのに十分な化合物の量を意味する。「有効量」は、化合物、治療される対象の疾患およびその重症度および年齢、体重、体調、および反応性によって様々であり、最終的には、対応した医者の裁量次第である。
以下の一般的な反応は、本発明の化合物の製造に用いることができる。
工程の全数は、少なく保つことができる。
<アセテート2a〜cの合成の一般的な方法。>
アセトン(10mL)中のフェノール1a〜c(1.0mmol)の攪拌溶液へ、K2CO3(3mmol、415mg)およびエチルブロモアセテートまたはエチル2−ブロモプロピオネート(1.1mmol)を添加し、反応混合物を5時間還流加熱した。次いで、その混合物をセライトでろ過し、有機溶媒を減圧下に蒸発させた。残渣をカラムクロマトグラフィーで精製した[EtOAc−石油エーテル(bp40−60℃)、1:9]。
1H NMR (200 MHz, CDCl3): δ 7.15-6.78 (m, 8H), 4.61 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H)。
1H NMR (200 MHz, CDCl3): δ 7.24 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 4.66 (q, J = 6.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.75 (t, J = 7.0 Hz, 2H), 1.62-1.42 (m, 5H), 1.41-1.05 (m, 9H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 171.7, 156.3, 132.1, 127.9, 115.4, 72.4, 61.0, 35.1, 31.1, 29.0, 28.1, 22.3, 18.3, 13.9, 13.8。
1H NMR (200 MHz, CDCl3): δ 6.84-6.65 (m, 4H), 4.62 (q, J = 6.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.85 (t, J = 6.6 Hz, 2H), 1.80-1.61 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.46-1.06 (m, 11H), 0.87 (t, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 172.3, 153.8, 151.4, 116.2, 115.1, 73.4, 68.2, 61.0, 31.6, 29.2, 28.9, 25.9, 22.5, 18.4, 13.9。
無水Et2O(10mL)中のエステル2a〜c(1mmol)の攪拌溶液に、DIBALH(2.5mL、2.5mmol、ヘキサン中1.0M)を0℃でAr雰囲気下に添加し、反応混合物を室温で2時間攪拌した。水を次いで添加し(5mL)、混合物を30分間攪拌し、セライトでろ過した。有機溶媒を減圧下に蒸発させ、残渣をカラムクロマトグラフィーで精製した[EtOAc−石油 エーテル(bp40−60℃),3:7]。
1H NMR (200 MHz, CDCl3): δ 7.07-6.76 (m, 8H), 4.10-3.84 (m, 4H), 2.94 (br s, 1H); 13C NMR (50 MHz, CDCl3): δ 160.6, 155.8, 154.6, 153.9, 150.8, 120.0, 119.1, 116.2,115.5, 69.6, 61.1。
1H NMR (200 MHz, CDCl3): δ 7.28 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.51-4.32 (m, 1H), 3.74-3.58 (m, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.68 (s, 1H), 1.66-1.46 (m, 2H), 1.45-1.12 (m, 9H), 0.85 (t, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 156.5, 132.5, 127.4, 116.4, 74.8, 65.9, 35.4, 31.2, 29.1, 28.3, 22.4, 15.6, 13.9。
1H NMR (200 MHz, CDCl3): δ 6.94-6.74 (m, 4H), 4.43-4.24 (m, 1H), 3.90 (t, J = 6.6 Hz, 2H), 3.75-3.60 (m, 2H), 2.77 (br s, 1H), 1.87-1.65 (m, 2H), 1.57-1.25 (m, 8H), 1.22 (d, J = 6.2 Hz, 3H), 0.91 (t, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3): δ 153.7, 151.3, 117.6, 115.2, 75.9, 68.4, 66.0, 31.7, 29.2, 29.0, 25.9, 22.5, 15.7, 14.0。
トルエン(3mL)およびEtOAc(3mL)の混合物中のアルコール3a〜c(1.0mmol)溶液に、水(0.5mL)中のNaBr(0.11g、1.1mmol)の溶液を添加し、次いで2,2,6,6−テトラメチルピペリジン−1−イルオキシ遊離基(TEMPO)(2.2mg,0.01mmol)を添加した。生じた二相システムを0℃に冷却し、そこへNaHCO3(0.25g,3mmol)を含有する0.35M NaOCl(3.1mL,1.1mmol)の水溶液を激しく攪拌しながら、0℃で1時間にわたって滴下して加えた。混合物をさらに15分間0℃で攪拌した後、EtOAc(10mL)およびH2O(10mL)を添加した。水層を分離して、EtOAc(2×10mL)で洗浄した。合わせた有機層を引き続いてKI(0.04g)を含有する5%クエン酸水(10mL)、10%Na2S2O3水溶液(10mL)、およびブラインで洗浄して、Na2SO4で乾燥させた。溶媒を減圧下で徐発させ、残渣を更なる精製なしに用いた。
1H NMR (200 MHz, CDCl3): δ 7.07-6.82 (m, 8H), 4.80 (t, J = 6.4 Hz, 1H), 4.26-4.06 (m, 2H), 0.94 (s, 9H), 0.24 (s, 3H), 0.20 (s, 3H)。
1H NMR (200 MHz, CDCl3): δ 7.30 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 5.37-5.28 (m, 1H), 4.57-4.48 (m, 1H), 2.83 (t, J = 7.0 Hz, 2H), 1.71-1.18 (m, 11H), 1.00-0.82 (m, 12H), 0.30-0.06 (m, 6H); 13C NMR (50 MHz, CDCl3): δ 156.9, 132.4, 132.3, 128.6, 118.4, 116.7, 116.5, 75.5, 74.7, 65.5, 65.2, 35.4, 35.3, 31.3, 29.2, 28.4, 25.4, 22.5, 15.4, 15.1, 14.0, -5.3, -5.4。
1H NMR (200 MHz, CDCl3): δ 6.95-6.76 (m, 4H), 4.66-4.47 (m, 1H), 4.46-4.25 (m, 1H), 3.92 (t, J = 6.6 Hz, 2H), 1.88-1.64 (m, 2H), 1.56-1.17 (m, 11H), 1.00-0.82 (m, 12H), 0.27-0.09 (m, 6H); 13C NMR (50 MHz, CDCl3): δ 154.2, 150.8, 117.8, 117.7, 115.3, 76.6, 75.7, 68.4, 65.3, 65.1, 31.7, 29.3, 29.0, 25.9, 25.4, 22.5, 15.5, 15.1, 14.0, -5.3, -5.4。
MeOH(4mL)中のニトリル4a〜c(1.0mmol)およびCH3COO-NH4 +(3.6mmol、277mg)の攪拌溶液に、HCl.H−L−Cys−OMe(3.0mmol、515mg)を添加し、混合物を室温で終夜攪拌した。有機溶媒を減圧下に蒸発させ、残渣をカラムクロマトグラフィーで精製した[EtOAc−石油エーテル(bp40−60℃),1:9]。
1H NMR (200 MHz, CDCl3): δ 7.39-6.42 (m, 8H), 5.34-4.74 (m, 2H), 4.42-3.21 (m, 7H), 1.56-0.50 (m, 9H), 0.35-(-0.08) (m, 6H)。
1H NMR (200 MHz, CDCl3): δ 7.40-7.17 (m, 2H), 6.96-6.68 (m, 2H), 5.28-5.03 (m, 1H), 4.90-4.77 (m, 1H), 4.76-4.56 (m, 1H), 3.79 (s, 3H), 3.58-3.28 (m, 2H), 2.79 (t, J = 7.0 Hz, 2H), 1.70-1.11 (m, 11H), 1.01-0.78 (m, 12H), 0.19-0.01 (m, 6H); 13C NMR (50 MHz, CDCl3): δ 179.8, 171.2, 156.4, 133.1, 132.7, 116.1, 78.3, 78.0, 76.4, 74.8, 74.6, 52.7, 35.9, 35.6, 33.8, 33.6, 31.3, 29.2, 28.4, 25.8, 25.7, 22.5, 18.2, 14.0, 13.9, -4.7, -5.3。
1H NMR (200 MHz, CDCl3): δ 6.92-6.73 (m, 4H), 5.25-5.05 (m, 1H), 4.89-4.76 (m, 1H), 4.69-4.49 (m, 1H), 3.89 (t, J = 6.6 Hz, 2H), 3.83-3.75 (m, 3H), 3.55-3.30 (m, 2H), 1.86-1.63 (m, 2H), 1.50-1.10 (m, 11H), 1.06-0.75 (m, 12H), 0.17-0.01 (m, 6H).
<チアゾール6a〜cの合成の一般的方法。>
CH2Cl2(20mL)中のチアゾリン5a〜d(1mmol)溶液に、BrCCl3(6.0mmol、0.59mL)およびDBU(6.0mmol、0.90mL)を0℃で添加した。反応を2時間0℃で攪拌し、室温で終夜攪拌した。有機溶媒を減圧下に蒸発させ、残渣をカラムクロマトグラフィーで精製した[EtOAc−石油エーテルbp40−60℃),1:9]。
1H NMR (200 MHz, CDCl3): δ 8.17 (s, 1H), 7.12-6.67 (m, 8H), 5.52-5.36 (m, 1H), 4.49-4.33 (m, 1H), 4.11-3.84 (m, 4H), 0.94 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H)。
1H NMR (200 MHz, CDCl3): δ 8.15 (s, 1H), 7.39-7.23 (m, 2H), 6.97-6.82 (m, 2H), 5.44-5.30 (m, 1H), 4.98-4.74 (m, 1H), 3.95 (s, 3H), 2.81 (t, J = 7.0 Hz, 2H), 1.69-1.09 (m, 11H), 1.05-0.77 (m, 12H), 0.22-(-0.02) (m, 6H); 13C NMR (50 MHz, CDCl3): δ 176.7, 161.2, 156.4, 146.9, 133.1, 132.8, 127.8, 116.2, 76.7, 74.7, 52.4, 35.6, 31.3, 29.2, 28.4, 25.8, 25.7, 25.5, 25.4, 22.5, 18.2, 14.0, 12.7, -4.5, -5.3.
メチル2−(1−((tert−ブチルジメチルシリル)オキシ)−2−(4−(ヘプチルオキシ)フェノキシ)プロピル)チアゾール−4−カルボキシレート(ジアステレオマーの混合物)(6c).収率65%;白色油;
1H NMR (200 MHz, CDCl3): δ 8.14 (s, 1H), 7.05-6.61 (m, 4H), 5.47-5.17 (m, 1H), 4.85-4.59 (m, 1H), 4.31-3.68 (m, 5H), 1.88-0.65 (m, 25H), 0.39-(-0.15) (m, 6H)。
化合物6a〜c(1.0mmol)をMeOH(10mL)中の2N HClの溶液で処理した。TLCが出発原料の完全な消失を示したのち、有機溶媒を減圧下に蒸発させ、残渣をエーテル/石油エーテル(bp40−60℃)から再結晶した。
1H NMR (200 MHz, CDCl3): δ 8.19 (s, 1H), 7.09-6.78 (m, 8H), 5.51-5.37 (m, 1H), 4.54-4.40 (m, 1H), 4.29-4.17 (m, 1H), 3.93 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 172.3, 161.7, 154.0, 151.4, 146.0, 136.2, 128.2, 120.0, 119.4, 119.2, 116.3, 115.9, 71.9, 70.7, 52.5。
1H NMR (200 MHz, CDCl3): δ 8.19 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.32 (d, J = 4.0 Hz, 1H), 4.95-4.80 (m, 1H), 3.95 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 1.69-1.50 (m, 2H), 1.49-1.12 (m, 9H), 0.88 (t, J = 6.6 Hz, 3H)。
無水CH2Cl2(10mL)中の化合物7a〜c(1mmol)の溶液に、デス・マーチンペルヨージナン添加し(1.5mmol,637mg)、混合物を1時間室温で攪拌した。有機溶媒を減圧下で蒸発させ、Et2O(30mL)を添加した。有機相をNa2S2O3(1.5g,9.5mmol)を含有する飽和NaHCO3水溶液(20mL)、H2O(20mL)で洗浄し、Na2SO4で乾燥し、有機溶媒を減圧下に蒸発させた。残渣を石油エーテル(bp40−60℃)/EtOAcを溶出液として用いてカラムクロマトグラフィーで精製した。
1H NMR (600 MHz, CDCl3): δ 8.52 (s, 1H), 7.03-6.90 (m, 8H), 5.59 (s, 2H), 4.01 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 187.5, 164.4, 161.0, 159.3, 157.7, 153.8, 151.8, 148.7, 133.6, 120.0, 119.5, 116.3, 116.1, 70.9, 52.8; C19H14FNNaO5S [M + Na]+で計算したHRMS (ESI): 410.0469。測定値: 410.0477。
1H NMR (600 MHz, CDCl3): δ 8.44 (s, 1H), 7.19 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 5.97 (q, J = 7.2 Hz, 1H), 3.93 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 1.68 (d, J = 7.2 Hz, 3H), 1.52-1.45 (m, 2H), 1.34-1.26 (m, 2H), 1.24-1.14 (m, 4H), 0.80 (t, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 191.4, 164.7, 161.1, 156.2, 148.8, 133.9, 132.4, 128.5, 116.1, 75.0, 52.7, 35.4, 31.3, 29.3, 28.4, 22.5, 18.6, 14.0; C20H26NO4S2 [M + H]+で計算したHRMS (ESI): 408.1298。測定値: 408.1291。
1H NMR (600 MHz, CDCl3): δ 8.50 (s, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 5.96 (q, J = 6.6 Hz, 1H), 4.01 (s, 3H), 3.87 (t, J = 6.6 Hz, 2H), 1.77-1.70 (m, 5H), 1.64-1.53 (m, 2H), 1.46-1.39 (m, 2H), 1.37-1.24 (m, 4H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 191.9, 164.9, 161.1, 154.1, 151.2, 148.7, 133.7, 117.0, 115.4, 76.0, 68.5, 52.7, 31.8, 29.3, 29.0, 26.0, 22.6, 18.6, 14.1; C21H27NNaO5S [M + Na]+で計算したHRMS (ESI): 428.1502。測定値: 428.1514。
前記明細書から、様々な用途および疾患に適合させるために、ここに説明した本発明への多様化および変更を行ってもよいことは、理解できるであろう。そのような実施形態は、また、以下の特許請求の範囲の範囲内である。
Claims (12)
- 式(I’)の化合物または、その塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグ。
R7は、R6について定義したとおりであるか;または、
R6およびR7は、これらと結合した原子と一緒になって、4つまでのR8基で任意に置換された、6員の芳香族もしくは非芳香族、飽和もしくは不飽和、炭素環式もしくはヘテロ原子含有(例えば、O、NまたはS含有)環を形成してもよく;
各R8は、R6について定義したとおりであるか、またはオキソであり;
R10は、C1-6アルキルであり;
Arは、C6-14アリール基であり、前記アリール基は、1以上のR9基で(好ましくはOに対してメタ位またはパラ位に)任意に置換されていてもよく;
各R9は、ハロ、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、SC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換され)、トリハロメチル、C1-10−アルコキシ、またはC1-10アルキルであり;
各qは、1〜3、好ましくは1であり;
各pは、0〜3である。] - 式(II’)の化合物またはその塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグ。
R6は、H、C1-6アルキル、−(CH2)pCOOH、−(CH2)pCOOC1-6アルキル、−(CH2)pCONH2、−(CH2)pCONHC1-6アルキル、−(CH2)pCON(C1-6アルキル)2であり、
R7は、R6について定義したとおりであるか;または
R6およびR7は、これらと結合した原子と一緒になって、4つまでのR8基で任意に置換された、6員の芳香族もしくは非芳香族、飽和もしくは不飽和、炭素環式もしくはヘテロ原子含有(例えば、O、NまたはS含有)環を形成してもよく;
各R8は、R6について定義したとおりであるか、またはオキソであり;
R11は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、前記アリール基は、1以上のR9基で(好ましくはOに対してメタ位またはパラ位に)置換されていており;
各R9は、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、OAr2、O(CH2)qAr2、SC1-10アルキル基、SAr2またはS(CH2)qAr2であり;
ここで、Ar2は、フェニル(1以上のハロで任意に置換され)、トリハロメチル、C1-10−アルコキシ、またはC1-10 アルキルであり;
各qは、1〜3であり、好ましくは1であり;
各pは、0〜3である。] - 式(III)の化合物またはその塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグ。
R11は、HまたはC1-6アルキルであり;
R12は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、前記アリール基は、1以上のR9基で(好ましくはOに対してメタ位またはパラ位に)任意に置換されていてもよく;
各R9は、ハロ、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
Ar2は、フェニル(1以上のハロで任意に置換された)であり、トリハロメチル、C1-10−アルコキシまたはC1-10アルキルであり;
各qは、1〜3であり;
点線は、任意の二重結合である。] - 式(IV)の化合物またはその塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグ。
R7は、HまたはC1-6アルキルであり;
R11は、HまたはC1-6アルキルであり;
Arは、C6-14アリール基であり、前記アリール基は、1以上のR9基で(好ましくはV1に対してメタ位またはパラ位に)任意に置換されてもよく;
Arは、C6-14アリール基であり、前記アリール基は、1以上のR9基で(好ましくはOに対してメタ位またはパラ位に)任意に置換されてもよく;
各R9は、ハロ、OH、CN、ニトロ、NH2、NHC1-6アルキル、N(C1-6アルキル)2、ハロC1-6アルキル、C6-10アリール基、C7-12アリールアルキル、C1-10アルキル基、C2-10−モノまたは多不飽和のアルケニル基、OC1-10アルキル基、−OC1-10アルキル−O−C10アルキル、−C1-10アルキル−O−C1-10アルキル、−OC2-10−モノまたは多不飽和のアルケニル基、OAr2、O(CH2)qAr2、SAr2またはS(CH2)qAr2であり;
Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシ、またはC1-10アルキルであり;
各qは、1〜3である。] - 式(IIc)の請求項2に記載の化合物またはその塩、エステル、溶媒和物、N−オキシドもしくはプロドラッグ。
R6は、H、C1-6アルキル、−(CH2)pCOOH、−(CH2)pCOOC1-6アルキル、−(CH2)pCONH2、−(CH2)pCONHC1-6アルキル、−(CH2)pCON(C1-6アルキル)2であり、
R9は、−OC1-10アルキル−O−C10アルキル、−OAr2、−O(CH2)qAr2、SAr2もしくはS(CH2)qAr2であるか、またはR9は、SC1-10アルキルであってもよく、
Ar2は、フェニル(1以上のハロで任意に置換された)、トリハロメチル、C1-10−アルコキシ、またはC1-10アルキルであり;
各qは、1〜3であり、好ましくは1であり;
各pは、0〜3である。] - アルキル基が、線状である先行する請求項のいずれかに記載の化合物。
- 治療における使用のための、先行する請求項のいずれかに記載の化合物。
- 慢性炎症状態または過剰増殖性疾患の治療において用いられるための、先行する請求項のいずれかに記載の化合物。
- 請求項1〜8に記載の化合物を含む医薬組成物。
- 患者における慢性炎症状態または過剰増殖性疾患を治療する方法であって、
治療が必要な患者へ、請求項1〜8に記載の化合物の有効量を投与することを含む方法。
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GB1413695.6 | 2014-08-01 | ||
GBGB1413695.6A GB201413695D0 (en) | 2014-08-01 | 2014-08-01 | Compound |
PCT/EP2015/067836 WO2016016472A1 (en) | 2014-08-01 | 2015-08-03 | 2-oxothiatole compounds having activity as cpla2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders |
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JP2021522251A (ja) * | 2018-04-24 | 2021-08-30 | アヴェクシン エーエス | 線維性疾患の治療のための2−オキソチアゾール組成物 |
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CN102647984B (zh) * | 2009-10-02 | 2015-03-25 | 埃维克辛公司 | 抗炎症的2-羰基噻唑和2-羰基恶唑 |
CN105102438B (zh) | 2013-01-29 | 2019-04-30 | 埃维克辛公司 | 抗炎症和抗肿瘤的2-氧代噻唑类和2-氧代噻吩类化合物 |
GB201413695D0 (en) | 2014-08-01 | 2014-09-17 | Avexxin As | Compound |
GB201604318D0 (en) * | 2016-03-14 | 2016-04-27 | Avexxin As | Combination therapy |
GB202117609D0 (en) | 2021-12-06 | 2022-01-19 | Coegin Pharma Ab | 2-Oxothiazole compositions for treatment of T-cell acute lymphoblastic leukaemia |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2021522251A (ja) * | 2018-04-24 | 2021-08-30 | アヴェクシン エーエス | 線維性疾患の治療のための2−オキソチアゾール組成物 |
JP7389053B2 (ja) | 2018-04-24 | 2023-11-29 | アヴェクシン エーエス | 線維性疾患の治療のための2-オキソチアゾール組成物 |
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KR20170031779A (ko) | 2017-03-21 |
GB201413695D0 (en) | 2014-09-17 |
US20170166589A1 (en) | 2017-06-15 |
CN107074840A (zh) | 2017-08-18 |
US20210101913A1 (en) | 2021-04-08 |
AU2015295220A1 (en) | 2017-03-09 |
CN107074840B (zh) | 2022-04-26 |
AU2019200129A1 (en) | 2019-01-31 |
AU2015295220B2 (en) | 2018-10-11 |
US20190345168A1 (en) | 2019-11-14 |
CA2956544A1 (en) | 2016-02-04 |
US10851114B2 (en) | 2020-12-01 |
EP3174873B1 (en) | 2020-04-15 |
US10150781B2 (en) | 2018-12-11 |
EP3174873A1 (en) | 2017-06-07 |
JP6647278B2 (ja) | 2020-02-14 |
WO2016016472A1 (en) | 2016-02-04 |
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